TBK1/ IKKε Inhibitors
View the TBK1/IKKε Inhibitor case study.
TANK-binding kinase 1 (TBK1) and IkappaB kinase epsilon (IKKε) have been validated as novel drug targets, with applications in the treatment of cancer, a variety of inflammatory diseases (including rheumatoid arthritis, COPD and psoriasis) and obesity.
Domainex has the most advanced drug discovery programme against these targets. It has identified first-in-class small molecule inhibitors of TBK1/IKKε and is progressing these as potential disease modifying therapies against COPD and psoriasis.
Domainex's compounds exhibit high potency in in vivo models of disease, are orally bioavailable and have excellent drug-like properties. Domainex has filed IP on the lead series and will progress to IND for the treatment of inflammatory diseases. Domainex now aims to raise investment or partner this programme, to progress through to clinical Proof of Concept. The first clinical trials will be in psoriasis patients.
Psoriasis is a common, chronic, relapsing/remitting, immune-mediated systemic disease characterized by skin lesions including red, scaly patches, papules, and plaques, which usually itch. The skin lesions seen in psoriasis may vary in severity from minor localized patches to complete body coverage.
For the treatment of severe symptoms, Amgen, Eli Lilly and Novartis each are in the midst of testing biologics that target a critical molecule in the immune system called IL-17 that has been linked to the skin inflammation of psoriasis. In each case, the drug so far is performing very well. About 80 percent of Phase II clinical trial patients achieved PASI (Psoriasis Area Severity Index) 75 percent, or their psoriasis has cleared by 75 percent in 12 weeks. As many as 60 percent of patients are completely clear in three months. However, these drugs are monoclonal antibodies (Mabs), which means i.v. adminstration in a hospital setting, which is costly and inconveniant.
Domainex's TBK1/IKKε inhibitors have been shown to disrupt IL17 and could offer an oral tablet alternative to the reported Mabs. Studies are ongoing to show in vivo effectiveness.
COPD is a serious respiratory disease in which patients suffer from a combination of chronic bronchitis, emphysema and small airway disease. It is a major and growing cause of illness and death in the UK and worldwide. Importantly, due to the mechanism of action of Domainex's TBK1/IKKe drug, we expect our drug for COPD to be disease-modifying; unlike current available treatments that merely provide symptomatic relief.
It is anticipated that inhibition of IKKε/TBK1 will lead to a more potent and profound effect on both the symptoms and progression of COPD. The basis for this expectation is that these kinases are at the nexus of several pathways, each of which is known to be a driver of the pathology of COPD. For example it has been clearly shown that IKKε is a key player in IL-17 signalling, through phosphorylation of Act1 which leads to the formation of a complex between the activated Act1 and TRAF 2 and 5. This leads to both increased levels and increased stabilisation of the mRNA of key pathogenic cytokines such as MAPK kinases and IL-6.
Similarly it is well established that IKKε also lies on the same pathway as p38 MAPK. This pro-inflammatory kinase is already an established target for COPD with several inhibitor programmes in development. Thus, inhibition of IKKε/TBK1, unlike other targets such as p38, will down-regulate numerous pathways that are involved in induction of pro-inflammatory cytokines. It is expected that such a unique spectrum of anti-inflammatory changes will have a profound effect on the pathology of COPD.
Domainex’s project is aimed at oral therapy. With the exception of Rofluimast (PDE4 inhibitor), no oral/systemic agents are available for treatment of COPD. Oral treatment has the advantage of delivering an anti-inflammatory effect systemically and to the lung.